Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk
| Autor: | Francisco Fueyo-González, Guillermo Vilanova, Mehek Ningoo, Nada Marjanovic, Juan A. González-Vera, Ángel Orte, Miguel Fribourg |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | iScience, Vol 26, Iss 12, Pp 108491- (2023) |
| Druh dokumentu: | article |
| ISSN: | 2589-0042 10881174 |
| DOI: | 10.1016/j.isci.2023.108491 |
| Popis: | Summary: Foxp3 acetylation is essential to regulatory T (Treg) cell stability and function, but pharmacologically increasing it remains an unmet challenge. Here, we report that small-molecule compounds that inhibit TIP60, an acetyltransferase known to acetylate Foxp3, unexpectedly increase Foxp3 acetylation and Treg induction. Utilizing a dual experimental/computational approach combined with a newly developed FRET-based methodology compatible with flow cytometry to measure Foxp3 acetylation, we unraveled the mechanism of action of these small-molecule compounds in murine and human Treg induction cell cultures. We demonstrate that at low-mid concentrations they activate TIP60 to acetylate P300, a different acetyltransferase, which in turn increases Foxp3 acetylation, thereby enhancing Treg cell induction. These results reveal a potential therapeutic target relevant to autoimmunity and transplant. |
| Databáze: | Directory of Open Access Journals |
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